Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0005789 endoplasmic reticulum membrane	IBA GO_REF:0000033	ACCEPT	Summary: Squalene synthase is a C-terminally anchored endoplasmic reticulum membrane protein; the phylogenetic IBA correctly places its active enzymatic location at the ER membrane. Reason: UniProt records the subcellular location as the endoplasmic reticulum membrane (multi-pass), consistent with the family-wide phylogenetic inference. This is a core aspect of the gene's biology. Supporting Evidence: file:human/FDFT1/FDFT1-uniprot.txt Endoplasmic reticulum membrane file:human/FDFT1/FDFT1-uniprot.txt Multi-pass membrane protein
GO:0051996 squalene synthase [NAD(P)H] activity	IBA GO_REF:0000033	ACCEPT	Summary: Core molecular function. FDFT1 is squalene synthase, catalysing the NAD(P)H-dependent condensation of two farnesyl diphosphate molecules to squalene (EC 2.5.1.21). Reason: The IBA is fully supported by experimental characterization of the human enzyme, including the crystal structure and catalytic assays. This is the defining core function of the gene. Supporting Evidence: PMID:10896663 through a reductive dimerization of two farnesyl diphosphate (FPP) file:human/FDFT1/FDFT1-uniprot.txt Catalyzes the condensation of 2 farnesyl pyrophosphate (FPP)
GO:0006695 cholesterol biosynthetic process	IBA GO_REF:0000033	ACCEPT	Summary: Squalene synthase catalyses the first committed step toward cholesterol; its product squalene is cyclised (via lanosterol) to cholesterol. Reason: Well supported: FPP conversion to squalene by SQS is the first committed step in cholesterol formation, and the human enzyme functionally complements sterol-deficient yeast. This is a core biological process for the gene. Supporting Evidence: PMID:10896663 squalene synthase represents the first committed PMID:10896663 Squalene synthase catalyzes the biosynthesis of squalene, a key
GO:0045338 farnesyl diphosphate metabolic process	IBA GO_REF:0000033	ACCEPT	Summary: FPP is the substrate of squalene synthase; the enzyme consumes two FPP molecules per catalytic cycle, so it participates in farnesyl diphosphate metabolism. Reason: Accurate: SQS is the enzyme that diverts FPP into the sterol branch, and FPP sits at the branch point of the isoprenoid pathway. This is correct though secondary to the squalene synthase activity/cholesterol biosynthesis annotations. Supporting Evidence: PMID:10896663 the final branch point in the isoprenoid biosynthesis pathway file:human/FDFT1/FDFT1-uniprot.txt Catalyzes the condensation of 2 farnesyl pyrophosphate (FPP)
GO:0005783 endoplasmic reticulum	IEA GO_REF:0000117	ACCEPT	Summary: Localizes to the endoplasmic reticulum. Correct but less precise than the ER membrane annotation. Reason: Consistent with the UniProt ER membrane subcellular location and with the IDA HPA immunofluorescence annotation to the ER. ER is a valid (broader) location. Supporting Evidence: file:human/FDFT1/FDFT1-uniprot.txt Endoplasmic reticulum membrane
GO:0005789 endoplasmic reticulum membrane	IEA GO_REF:0000044	ACCEPT	Summary: ER membrane localization, mapped from the UniProt subcellular location keyword. Reason: Matches the curated UniProt subcellular location; SQS is a multi-pass ER membrane protein. Core localization. Supporting Evidence: file:human/FDFT1/FDFT1-uniprot.txt Endoplasmic reticulum membrane
GO:0006694 steroid biosynthetic process	IEA GO_REF:0000117	ACCEPT	Summary: Broad parent term covering sterol/cholesterol biosynthesis. True but less specific than cholesterol biosynthetic process. Reason: Correct as a broader classification of the gene's role in sterol/cholesterol synthesis; retained but not the most informative BP term (see GO:0006695). Supporting Evidence: file:human/FDFT1/FDFT1-uniprot.txt It is the first committed enzyme of the sterol biosynthesis pathway
GO:0008610 lipid biosynthetic process	IEA GO_REF:0000002	ACCEPT	Summary: Very general parent term (sterols are lipids). True but uninformative relative to the cholesterol/sterol biosynthesis annotations. Reason: Not incorrect: cholesterol biosynthesis is a lipid biosynthetic process. Retained as a high-level classification; the more specific terms carry the biology. Supporting Evidence: file:human/FDFT1/FDFT1-uniprot.txt It is the first committed enzyme of the sterol biosynthesis pathway
GO:0016020 membrane	IEA GO_REF:0000117	ACCEPT	Summary: Generic membrane localization; SQS is a multi-pass membrane protein. Correct but far less specific than endoplasmic reticulum membrane. Reason: True but a high-level parent of the ER membrane annotation. Retained; the ER membrane term is the informative one. Supporting Evidence: file:human/FDFT1/FDFT1-uniprot.txt Multi-pass membrane protein
GO:0016765 transferase activity, transferring alkyl or aryl (other than methyl) groups	IEA GO_REF:0000002	ACCEPT	Summary: Parent MF term corresponding to EC 2.5.1.- (alkyl/aryl transferases); squalene synthase (EC 2.5.1.21) is a member. Correct but general. Reason: An InterPro2GO mapping to the correct enzymatic superclass. It is accurate but subsumed by the specific squalene synthase [NAD(P)H] activity term (GO:0051996). Supporting Evidence: file:human/FDFT1/FDFT1-uniprot.txt EC=2.5.1.21
GO:0045338 farnesyl diphosphate metabolic process	IEA GO_REF:0000002	ACCEPT	Summary: InterPro-based duplicate of the IBA farnesyl diphosphate metabolic process annotation; FPP is the substrate of SQS. Reason: Correct; consistent with the IBA annotation to the same term. SQS consumes FPP. Supporting Evidence: file:human/FDFT1/FDFT1-uniprot.txt Catalyzes the condensation of 2 farnesyl pyrophosphate (FPP)
GO:0051996 squalene synthase [NAD(P)H] activity	IEA GO_REF:0000120	ACCEPT	Summary: Automated (RHEA/EC 2.5.1.21) mapping to the core squalene synthase activity. Duplicate of the experimentally-supported EXP/IBA annotations. Reason: Correctly recapitulates the core molecular function from RHEA:32295/32299 and EC 2.5.1.21. Supporting Evidence: file:human/FDFT1/FDFT1-uniprot.txt EC=2.5.1.21
GO:0005515 protein binding	IPI PMID:23864651 The identification of novel proteins that interact with the ...	MARK AS OVER ANNOTATED	Summary: FDFT1/SQS was identified as one of many candidate interactors of the GLP-1 receptor in a membrane split-ubiquitin yeast two-hybrid / CO-IP screen. This is a generic protein-binding annotation with no specific molecular function attached. Reason: Bare protein binding (GO:0005515) is uninformative and, here, derives from a high-throughput GLP-1R interactome screen in which SQS is a co-detected membrane partner; it does not describe the enzyme's function. Per curation policy, marked as over-annotated rather than removed. Supporting Evidence: PMID:23864651 identify proteins that interact with the GLP-1R
GO:0005515 protein binding	IPI PMID:25910212 Widespread macromolecular interaction perturbations in human...	MARK AS OVER ANNOTATED	Summary: Protein-binding annotation arising from an interactome-scale edgotyping study of Mendelian disease alleles. Generic and uninformative for FDFT1 molecular function. Reason: Bare protein binding from a systematic interaction-perturbation dataset; no specific binding partner/function is established for SQS beyond an entry in a large interaction map. Marked as over-annotated per policy (not removed). Supporting Evidence: PMID:25910212 two-thirds of disease-associated alleles perturb protein-protein
GO:0005515 protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	MARK AS OVER ANNOTATED	Summary: Multiple binary interactions for FDFT1 from HuRI (human reference interactome, Y2H). Many partners are ER/membrane proteins, consistent with an ER-membrane enzyme, but no specific molecular function is defined by these bare protein-binding calls. Reason: Bare protein binding (GO:0005515) from a proteome-scale binary interactome; uninformative regarding SQS function. Marked as over-annotated rather than removed, per curation policy. Supporting Evidence: PMID:32296183 reference interactome map of human binary protein interactions
GO:0005783 endoplasmic reticulum	IDA GO_REF:0000052	ACCEPT	Summary: Direct immunofluorescence (Human Protein Atlas) localizes FDFT1 to the endoplasmic reticulum. Reason: Experimental (IDA) localization consistent with the curated ER membrane subcellular location. Supports the core ER localization. Supporting Evidence: file:human/FDFT1/FDFT1-uniprot.txt Endoplasmic reticulum membrane
GO:0005789 endoplasmic reticulum membrane	ISS GO_REF:0000024	ACCEPT	Summary: ER membrane localization inferred by sequence similarity to an ortholog (UniProtKB:Q02769, rat SQS). Consistent with all other localization evidence. Reason: Curator-judged sequence-similarity transfer of the ER membrane location; agrees with the IBA, IDA (ER), TAS (Reactome), and IEA annotations. Core localization. Supporting Evidence: file:human/FDFT1/FDFT1-uniprot.txt Endoplasmic reticulum membrane
GO:0051996 squalene synthase [NAD(P)H] activity	EXP PMID:10896663 Crystal structure of human squalene synthase. A key enzyme i...	ACCEPT	Summary: Experimental determination of squalene synthase catalytic activity on the human enzyme, accompanying its crystal structure: reductive dimerization of two FPP molecules to squalene. Reason: Direct experimental support (EXP) for the defining molecular function from the human SQS crystal-structure/catalysis study. This is the anchor experimental annotation for the core function. Supporting Evidence: PMID:10896663 through a reductive dimerization of two farnesyl diphosphate (FPP) PMID:10896663 Squalene synthase catalyzes the biosynthesis of squalene, a key
GO:0005789 endoplasmic reticulum membrane	TAS Reactome:R-HSA-1655850	ACCEPT	Summary: Reactome (FDFT1 expression event) places the enzyme at the ER membrane. Consistent with all other localization evidence. Reason: Traceable author statement from Reactome agreeing with the curated ER membrane location. Supporting Evidence: Reactome:R-HSA-1655850 The FDFT1 gene is transcribed to yield mRNA
GO:0005789 endoplasmic reticulum membrane	TAS Reactome:R-HSA-191402	ACCEPT	Summary: Reactome reaction (reduction of presqualene diphosphate to squalene) is annotated to the ER membrane, where SQS acts. Reason: Reactome TAS for the second half-reaction of squalene synthesis, consistent with the ER membrane localization of the enzyme. Supporting Evidence: Reactome:R-HSA-191402 catalyzes the reduction of presqualene diphosphate (PSQPP) to squalene
GO:0005789 endoplasmic reticulum membrane	TAS Reactome:R-HSA-191405	ACCEPT	Summary: Reactome reaction (dimerization of two FPP molecules to presqualene diphosphate) at the ER membrane, catalysed by FDFT1. Reason: Reactome TAS for the first half-reaction of squalene synthesis, consistent with the ER membrane localization of the enzyme. Supporting Evidence: Reactome:R-HSA-191405 catalyzes the reductive dimerization of two farnesyl diphosphate (FAPP) molecules to form
GO:0006694 steroid biosynthetic process	TAS PMID:8474436 Conservation between human and fungal squalene synthetases: ...	ACCEPT	Summary: SQS is a major control point of sterol biosynthesis; human/yeast/fungal enzymes are conserved and the human enzyme rescues sterol-deficient yeast. Steroid (sterol) biosynthesis is a broad but accurate BP. Reason: Traceable author statement supported by demonstrated conservation and functional complementation. Correct though broader than the cholesterol biosynthetic process term. Supporting Evidence: PMID:8474436 is thought to represent a major control point PMID:8474436 reversed the ergosterol requirement of S.
GO:0016020 membrane	TAS PMID:8474436 Conservation between human and fungal squalene synthetases: ...	ACCEPT	Summary: SQS is predicted/shown to be a C-terminal membrane-spanning protein. Generic membrane term; the ER membrane annotations are more specific. Reason: Traceable author statement; correct that SQS is a membrane protein. Subsumed by the ER membrane annotations, which carry the informative localization. Supporting Evidence: PMID:8474436 C-terminal membrane-spanning proteins of approximately 50

Core Functions

Squalene synthase: catalyses the NAD(P)H- and Mg2+-dependent reductive condensation of two molecules of farnesyl diphosphate to squalene (via presqualene diphosphate), the first committed step of sterol biosynthesis, at the endoplasmic reticulum membrane.

Molecular Function:

squalene synthase [NAD(P)H] activity

Directly Involved In:

cholesterol biosynthetic process

Cellular Locations:

endoplasmic reticulum membrane

Supporting Evidence:

PMID:10896663
through a reductive dimerization of two farnesyl diphosphate (FPP)
file:human/FDFT1/FDFT1-uniprot.txt
Catalyzes the condensation of 2 farnesyl pyrophosphate (FPP)

References

GO_REF:0000002

Gene Ontology annotation through association of InterPro records with GO terms

GO_REF:0000024

Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity

GO_REF:0000033

Annotation inferences using phylogenetic trees

GO_REF:0000044

Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt

GO_REF:0000052

Gene Ontology annotation based on curation of immunofluorescence data

GO_REF:0000117

Electronic Gene Ontology annotations created by ARBA machine learning models

GO_REF:0000120

Combined Automated Annotation using Multiple IEA Methods

PMID:10896663

Crystal structure of human squalene synthase. A key enzyme in cholesterol biosynthesis.

Human squalene synthase catalyses biosynthesis of squalene through reductive dimerization of two FPP molecules; conversion of FPP to squalene is the first committed step in cholesterol formation.

"through a reductive dimerization of two farnesyl diphosphate (FPP)"

PMID:23864651

The identification of novel proteins that interact with the GLP-1 receptor and restrain its activity.

PMID:25910212

Widespread macromolecular interaction perturbations in human genetic disorders.

PMID:32296183

A reference map of the human binary protein interactome.

PMID:8474436

Conservation between human and fungal squalene synthetases: similarities in structure, function, and regulation.

Squalene synthetase (EC 2.5.1.21) is a major control point of isoprene and sterol biosynthesis; the human enzyme is a C-terminal membrane-spanning ~50 kDa protein and functionally complements sterol-deficient (ERG9) yeast.

"is thought to represent a major control point"

Reactome:R-HSA-1655850

Expression of Farnesyldiphosphate Farnesyltransferase (FDFT1, Squalene Synthase)

Reactome:R-HSA-191402

Reduction of presqualene diphosphate to form squalene

Reactome:R-HSA-191405

Two FAPP molecules dimerize to form presqualene diphosphate

file:human/FDFT1/FDFT1-uniprot.txt

UniProtKB P37268 (FDFT_HUMAN) entry - Squalene synthase

📚 Additional Documentation

Notes

(FDFT1-notes.md)

FDFT1 (Squalene synthase / farnesyl-diphosphate farnesyltransferase 1) review notes

UniProtKB: P37268 | HGNC:3629 | EC 2.5.1.21 | Human (NCBITaxon:9606)

Function (verified)

FDFT1 is squalene synthase (SQS/SS), also called farnesyl-diphosphate
farnesyltransferase 1 (FPP:FPP farnesyltransferase). It catalyses the first
committed step of sterol biosynthesis: the reductive head-to-head (1'-1)
condensation of two molecules of farnesyl diphosphate (FPP) to squalene,
proceeding via a stable presqualene diphosphate (PSQPP) intermediate and an
NAD(P)H-dependent reduction.

UniProt FUNCTION [file:human/FDFT1/FDFT1-uniprot.txt]: "Catalyzes the condensation
of 2 farnesyl pyrophosphate (FPP) moieties to form squalene. Proceeds in two
distinct steps. In the first half-reaction, two molecules of FPP react to form the
stable presqualene diphosphate intermediate (PSQPP) ... In the second half-reaction,
PSQPP undergoes heterolysis, isomerization, and reduction with NADPH or NADH to form
squalene. It is the first committed enzyme of the sterol biosynthesis pathway."
Catalytic activity (Rhea:RHEA:32295, EC 2.5.1.21): 2 (2E,6E)-farnesyl diphosphate +
NADPH + H+ = squalene + 2 diphosphate + NADP+. Also uses NADH (RHEA:32299).
Requires Mg2+ cofactor (PubMed:24531458).
PATHWAY (UniProt): Terpene metabolism; lanosterol biosynthesis; lanosterol from
farnesyl diphosphate: step 1/3.
PMID:10896663 and "Because FPP is located at the final branch point in the
isoprenoid biosynthesis pathway, its conversion to squalene through the action of
squalene synthase represents the first committed step in the formation of cholesterol"
— establishes both the reaction and the branch-point/committed-step role. This is the
human SQS crystal structure paper (2.15 A, residues 39-370).
PMID:24531458 structural insights into catalytic mechanism, Mg2+/NADP binding sites
(abstract not cached; used as ECO:0000269 support in UniProt for the reactions).
PMID:8474436 Human/yeast conservation; human
cDNA can rescue S. cerevisiae ERG9 disruption; predicted C-terminal membrane-spanning
~50 kDa protein.

Branch point biology

FPP sits at the branch point of the isoprenoid pathway. SQS commits FPP specifically to
the sterol branch (squalene -> lanosterol -> cholesterol), diverting it away from the
non-sterol branches (dolichol, ubiquinone/CoQ, heme A, protein prenylation). This makes
SQS a pharmacological target (statin-sparing lipid-lowering; inhibitors TAK-475/lapaquistat,
zaragozic acids) that lowers sterol synthesis without depleting the non-sterol isoprenoids
depleted by HMG-CoA reductase inhibition.

Localization

C-terminally anchored endoplasmic reticulum membrane protein.
- UniProt SUBCELLULAR LOCATION: "Endoplasmic reticulum membrane ... Multi-pass membrane
protein" (two C-terminal TM helices, FT TRANSMEM 284-304 and 384-404; the catalytic
domain 31-370 is cytosolic-facing, consistent with the ER GO:0098554 cytoplasmic-side
annotation).
- GOA has IDA (HPA immunofluorescence, GO_REF:0000052) to endoplasmic reticulum, plus
IBA/ISS/TAS/IEA to ER membrane. HPA reports low tissue specificity; widely expressed.

Disease

Squalene synthase deficiency (SQSD; MIM:618156) — autosomal recessive congenital
disorder of cholesterol biosynthesis. PMID:29909962 (Coman et al. 2018, Am J Hum Genet)
first characterised it: profound developmental delay, brain abnormalities, 2/3 syndactyly
of toes, facial dysmorphism, low total and LDL cholesterol, abnormal urine organic acids
(heptadecanoid / methylsuccinate features from accumulated FPP-derived metabolites). SLOS-like.
UniProt DISEASE + TISSUE SPECIFICITY (widely expressed) cite this paper. (Abstract not cached;
used only as background, not as supporting_text.)

Protein-protein interactions (IPI, GO:0005515)

GOA carries many protein binding (GO:0005515) IPI annotations from high-throughput
interactome maps. These are bare protein-binding and per policy should be
MARK_AS_OVER_ANNOTATED (not informative; not core function; not removed).
- PMID:23864651 — GLP-1R interactome (MYTH split-ubiquitin Y2H + CO-IP). FDFT1/SQS
(P37268) appears as one of many GLP-1R (P43220) interactors; membrane-based screen. No
functional consequence for SQS shown.
- PMID:25910212 — "Widespread macromolecular interaction perturbations in human genetic
disorders" (edgotyping); interactome-scale.
- PMID:32296183 — HuRI, the human binary reference interactome (Y2H). FDFT1 shown to bind
~16 partners (AQP6, ARL13B, CD74, CD79A, CLN5, CREB3, ELOVL4, FAM209A, GJA8, GPR152,
JAGN1, NCAPH2, PANX1, SLC10A1, SLC35C2, TLCD4, TMX2 in UniProt INTERACTION block). Many
are ER/membrane proteins; consistent with an ER-membrane enzyme co-detected in
membrane-Y2H, but none establish a specific molecular function beyond catalysis.

Annotation-set assessment (GOA, P37268)

Core (ACCEPT):
- GO:0051996 squalene synthase [NAD(P)H] activity — MF, has EXP (PMID:10896663), IBA, IEA
- GO:0006695 cholesterol biosynthetic process — BP, IBA
- GO:0005789 endoplasmic reticulum membrane — CC, IBA is_active_in + ISS/TAS/IEA located_in
- GO:0005783 endoplasmic reticulum — CC, IDA (HPA)

Accept (correct, broader or context):
- GO:0045338 farnesyl diphosphate metabolic process — BP (FPP is the substrate)
- GO:0006694 steroid biosynthetic process — BP (broad parent of sterol/cholesterol biosynth)
- GO:0008610 lipid biosynthetic process — BP (broad but true)
- GO:0016765 transferase, transferring alkyl/aryl (other than methyl) groups — MF (EC 2.5.1.-
parent of the squalene-synthase activity; correct but general)
- GO:0016020 membrane — CC (general; true)

MARK_AS_OVER_ANNOTATED:
- GO:0005515 protein binding (x3 PMIDs) — bare protein binding, uninformative HT interactome.

📄 View Raw YAML

id: P37268
gene_symbol: FDFT1
product_type: PROTEIN
status: INITIALIZED
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  FDFT1 encodes squalene synthase (SQS; farnesyl-diphosphate farnesyltransferase 1;
  EC 2.5.1.21), the enzyme that catalyses the first committed step of sterol
  biosynthesis. It performs the reductive, head-to-head condensation of two molecules
  of farnesyl diphosphate (FPP) to form squalene, proceeding in two half-reactions via
  the stable presqualene diphosphate (PSQPP) intermediate followed by an NAD(P)H- and
  Mg2+-dependent reduction. Because FPP lies at the branch point of the isoprenoid
  pathway, squalene synthase commits the isoprenoid pool specifically to the sterol
  branch (squalene to lanosterol to cholesterol), diverting it away from the non-sterol
  branches (dolichol, ubiquinone, heme A, and protein prenylation). The protein is a
  C-terminally anchored, multi-pass endoplasmic reticulum membrane enzyme with its
  catalytic domain facing the cytoplasm. Squalene synthase is widely expressed, is a
  pharmacological target for cholesterol lowering, and biallelic loss-of-function causes
  squalene synthase deficiency (SQSD), a congenital disorder of cholesterol biosynthesis
  featuring developmental delay, facial dysmorphism, and low total/LDL cholesterol.
existing_annotations:
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: >-
      Squalene synthase is a C-terminally anchored endoplasmic reticulum membrane protein;
      the phylogenetic IBA correctly places its active enzymatic location at the ER membrane.
    action: ACCEPT
    reason: >-
      UniProt records the subcellular location as the endoplasmic reticulum membrane
      (multi-pass), consistent with the family-wide phylogenetic inference. This is a
      core aspect of the gene's biology.
    supported_by:
    - reference_id: file:human/FDFT1/FDFT1-uniprot.txt
      supporting_text: Endoplasmic reticulum membrane
    - reference_id: file:human/FDFT1/FDFT1-uniprot.txt
      supporting_text: Multi-pass membrane protein
- term:
    id: GO:0051996
    label: squalene synthase [NAD(P)H] activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: >-
      Core molecular function. FDFT1 is squalene synthase, catalysing the NAD(P)H-dependent
      condensation of two farnesyl diphosphate molecules to squalene (EC 2.5.1.21).
    action: ACCEPT
    reason: >-
      The IBA is fully supported by experimental characterization of the human enzyme,
      including the crystal structure and catalytic assays. This is the defining core
      function of the gene.
    supported_by:
    - reference_id: PMID:10896663
      supporting_text: through a reductive dimerization of two farnesyl diphosphate (FPP)
    - reference_id: file:human/FDFT1/FDFT1-uniprot.txt
      supporting_text: Catalyzes the condensation of 2 farnesyl pyrophosphate (FPP)
- term:
    id: GO:0006695
    label: cholesterol biosynthetic process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: >-
      Squalene synthase catalyses the first committed step toward cholesterol; its product
      squalene is cyclised (via lanosterol) to cholesterol.
    action: ACCEPT
    reason: >-
      Well supported: FPP conversion to squalene by SQS is the first committed step in
      cholesterol formation, and the human enzyme functionally complements sterol-deficient
      yeast. This is a core biological process for the gene.
    supported_by:
    - reference_id: PMID:10896663
      supporting_text: squalene synthase represents the first committed
    - reference_id: PMID:10896663
      supporting_text: Squalene synthase catalyzes the biosynthesis of squalene, a key
- term:
    id: GO:0045338
    label: farnesyl diphosphate metabolic process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: >-
      FPP is the substrate of squalene synthase; the enzyme consumes two FPP molecules per
      catalytic cycle, so it participates in farnesyl diphosphate metabolism.
    action: ACCEPT
    reason: >-
      Accurate: SQS is the enzyme that diverts FPP into the sterol branch, and FPP sits at
      the branch point of the isoprenoid pathway. This is correct though secondary to the
      squalene synthase activity/cholesterol biosynthesis annotations.
    supported_by:
    - reference_id: PMID:10896663
      supporting_text: the final branch point in the isoprenoid biosynthesis pathway
    - reference_id: file:human/FDFT1/FDFT1-uniprot.txt
      supporting_text: Catalyzes the condensation of 2 farnesyl pyrophosphate (FPP)
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: located_in
  review:
    summary: >-
      Localizes to the endoplasmic reticulum. Correct but less precise than the ER membrane
      annotation.
    action: ACCEPT
    reason: >-
      Consistent with the UniProt ER membrane subcellular location and with the IDA HPA
      immunofluorescence annotation to the ER. ER is a valid (broader) location.
    supported_by:
    - reference_id: file:human/FDFT1/FDFT1-uniprot.txt
      supporting_text: Endoplasmic reticulum membrane
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: >-
      ER membrane localization, mapped from the UniProt subcellular location keyword.
    action: ACCEPT
    reason: >-
      Matches the curated UniProt subcellular location; SQS is a multi-pass ER membrane
      protein. Core localization.
    supported_by:
    - reference_id: file:human/FDFT1/FDFT1-uniprot.txt
      supporting_text: Endoplasmic reticulum membrane
- term:
    id: GO:0006694
    label: steroid biosynthetic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: involved_in
  review:
    summary: >-
      Broad parent term covering sterol/cholesterol biosynthesis. True but less specific
      than cholesterol biosynthetic process.
    action: ACCEPT
    reason: >-
      Correct as a broader classification of the gene's role in sterol/cholesterol
      synthesis; retained but not the most informative BP term (see GO:0006695).
    supported_by:
    - reference_id: file:human/FDFT1/FDFT1-uniprot.txt
      supporting_text: It is the first committed enzyme of the sterol biosynthesis pathway
- term:
    id: GO:0008610
    label: lipid biosynthetic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: >-
      Very general parent term (sterols are lipids). True but uninformative relative to the
      cholesterol/sterol biosynthesis annotations.
    action: ACCEPT
    reason: >-
      Not incorrect: cholesterol biosynthesis is a lipid biosynthetic process. Retained as a
      high-level classification; the more specific terms carry the biology.
    supported_by:
    - reference_id: file:human/FDFT1/FDFT1-uniprot.txt
      supporting_text: It is the first committed enzyme of the sterol biosynthesis pathway
- term:
    id: GO:0016020
    label: membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: located_in
  review:
    summary: >-
      Generic membrane localization; SQS is a multi-pass membrane protein. Correct but far
      less specific than endoplasmic reticulum membrane.
    action: ACCEPT
    reason: >-
      True but a high-level parent of the ER membrane annotation. Retained; the ER membrane
      term is the informative one.
    supported_by:
    - reference_id: file:human/FDFT1/FDFT1-uniprot.txt
      supporting_text: Multi-pass membrane protein
- term:
    id: GO:0016765
    label: transferase activity, transferring alkyl or aryl (other than methyl) groups
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: >-
      Parent MF term corresponding to EC 2.5.1.- (alkyl/aryl transferases); squalene synthase
      (EC 2.5.1.21) is a member. Correct but general.
    action: ACCEPT
    reason: >-
      An InterPro2GO mapping to the correct enzymatic superclass. It is accurate but subsumed
      by the specific squalene synthase [NAD(P)H] activity term (GO:0051996).
    supported_by:
    - reference_id: file:human/FDFT1/FDFT1-uniprot.txt
      supporting_text: EC=2.5.1.21
- term:
    id: GO:0045338
    label: farnesyl diphosphate metabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: >-
      InterPro-based duplicate of the IBA farnesyl diphosphate metabolic process annotation;
      FPP is the substrate of SQS.
    action: ACCEPT
    reason: >-
      Correct; consistent with the IBA annotation to the same term. SQS consumes FPP.
    supported_by:
    - reference_id: file:human/FDFT1/FDFT1-uniprot.txt
      supporting_text: Catalyzes the condensation of 2 farnesyl pyrophosphate (FPP)
- term:
    id: GO:0051996
    label: squalene synthase [NAD(P)H] activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: >-
      Automated (RHEA/EC 2.5.1.21) mapping to the core squalene synthase activity. Duplicate of
      the experimentally-supported EXP/IBA annotations.
    action: ACCEPT
    reason: >-
      Correctly recapitulates the core molecular function from RHEA:32295/32299 and EC 2.5.1.21.
    supported_by:
    - reference_id: file:human/FDFT1/FDFT1-uniprot.txt
      supporting_text: EC=2.5.1.21
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:23864651
  qualifier: enables
  review:
    summary: >-
      FDFT1/SQS was identified as one of many candidate interactors of the GLP-1 receptor in a
      membrane split-ubiquitin yeast two-hybrid / CO-IP screen. This is a generic protein-binding
      annotation with no specific molecular function attached.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Bare protein binding (GO:0005515) is uninformative and, here, derives from a
      high-throughput GLP-1R interactome screen in which SQS is a co-detected membrane partner;
      it does not describe the enzyme's function. Per curation policy, marked as over-annotated
      rather than removed.
    supported_by:
    - reference_id: PMID:23864651
      supporting_text: identify proteins that interact with the GLP-1R
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25910212
  qualifier: enables
  review:
    summary: >-
      Protein-binding annotation arising from an interactome-scale edgotyping study of Mendelian
      disease alleles. Generic and uninformative for FDFT1 molecular function.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Bare protein binding from a systematic interaction-perturbation dataset; no specific binding
      partner/function is established for SQS beyond an entry in a large interaction map. Marked as
      over-annotated per policy (not removed).
    supported_by:
    - reference_id: PMID:25910212
      supporting_text: two-thirds of disease-associated alleles perturb protein-protein
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    summary: >-
      Multiple binary interactions for FDFT1 from HuRI (human reference interactome, Y2H). Many
      partners are ER/membrane proteins, consistent with an ER-membrane enzyme, but no specific
      molecular function is defined by these bare protein-binding calls.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Bare protein binding (GO:0005515) from a proteome-scale binary interactome; uninformative
      regarding SQS function. Marked as over-annotated rather than removed, per curation policy.
    supported_by:
    - reference_id: PMID:32296183
      supporting_text: reference interactome map of human binary protein interactions
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    summary: >-
      Direct immunofluorescence (Human Protein Atlas) localizes FDFT1 to the endoplasmic reticulum.
    action: ACCEPT
    reason: >-
      Experimental (IDA) localization consistent with the curated ER membrane subcellular location.
      Supports the core ER localization.
    supported_by:
    - reference_id: file:human/FDFT1/FDFT1-uniprot.txt
      supporting_text: Endoplasmic reticulum membrane
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: located_in
  review:
    summary: >-
      ER membrane localization inferred by sequence similarity to an ortholog (UniProtKB:Q02769,
      rat SQS). Consistent with all other localization evidence.
    action: ACCEPT
    reason: >-
      Curator-judged sequence-similarity transfer of the ER membrane location; agrees with the IBA,
      IDA (ER), TAS (Reactome), and IEA annotations. Core localization.
    supported_by:
    - reference_id: file:human/FDFT1/FDFT1-uniprot.txt
      supporting_text: Endoplasmic reticulum membrane
- term:
    id: GO:0051996
    label: squalene synthase [NAD(P)H] activity
  evidence_type: EXP
  original_reference_id: PMID:10896663
  qualifier: enables
  review:
    summary: >-
      Experimental determination of squalene synthase catalytic activity on the human enzyme,
      accompanying its crystal structure: reductive dimerization of two FPP molecules to squalene.
    action: ACCEPT
    reason: >-
      Direct experimental support (EXP) for the defining molecular function from the human SQS
      crystal-structure/catalysis study. This is the anchor experimental annotation for the core
      function.
    supported_by:
    - reference_id: PMID:10896663
      supporting_text: through a reductive dimerization of two farnesyl diphosphate (FPP)
    - reference_id: PMID:10896663
      supporting_text: Squalene synthase catalyzes the biosynthesis of squalene, a key
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-1655850
  qualifier: located_in
  review:
    summary: >-
      Reactome (FDFT1 expression event) places the enzyme at the ER membrane. Consistent with all
      other localization evidence.
    action: ACCEPT
    reason: >-
      Traceable author statement from Reactome agreeing with the curated ER membrane location.
    supported_by:
    - reference_id: Reactome:R-HSA-1655850
      supporting_text: The FDFT1 gene is transcribed to yield mRNA
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-191402
  qualifier: located_in
  review:
    summary: >-
      Reactome reaction (reduction of presqualene diphosphate to squalene) is annotated to the ER
      membrane, where SQS acts.
    action: ACCEPT
    reason: >-
      Reactome TAS for the second half-reaction of squalene synthesis, consistent with the ER
      membrane localization of the enzyme.
    supported_by:
    - reference_id: Reactome:R-HSA-191402
      supporting_text: catalyzes the reduction of presqualene diphosphate (PSQPP) to squalene
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-191405
  qualifier: located_in
  review:
    summary: >-
      Reactome reaction (dimerization of two FPP molecules to presqualene diphosphate) at the ER
      membrane, catalysed by FDFT1.
    action: ACCEPT
    reason: >-
      Reactome TAS for the first half-reaction of squalene synthesis, consistent with the ER
      membrane localization of the enzyme.
    supported_by:
    - reference_id: Reactome:R-HSA-191405
      supporting_text: catalyzes the reductive dimerization of two farnesyl diphosphate (FAPP) molecules to form
- term:
    id: GO:0006694
    label: steroid biosynthetic process
  evidence_type: TAS
  original_reference_id: PMID:8474436
  qualifier: involved_in
  review:
    summary: >-
      SQS is a major control point of sterol biosynthesis; human/yeast/fungal enzymes are conserved
      and the human enzyme rescues sterol-deficient yeast. Steroid (sterol) biosynthesis is a broad
      but accurate BP.
    action: ACCEPT
    reason: >-
      Traceable author statement supported by demonstrated conservation and functional
      complementation. Correct though broader than the cholesterol biosynthetic process term.
    supported_by:
    - reference_id: PMID:8474436
      supporting_text: is thought to represent a major control point
    - reference_id: PMID:8474436
      supporting_text: reversed the ergosterol requirement of S.
- term:
    id: GO:0016020
    label: membrane
  evidence_type: TAS
  original_reference_id: PMID:8474436
  qualifier: located_in
  review:
    summary: >-
      SQS is predicted/shown to be a C-terminal membrane-spanning protein. Generic membrane term;
      the ER membrane annotations are more specific.
    action: ACCEPT
    reason: >-
      Traceable author statement; correct that SQS is a membrane protein. Subsumed by the ER
      membrane annotations, which carry the informative localization.
    supported_by:
    - reference_id: PMID:8474436
      supporting_text: C-terminal membrane-spanning proteins of approximately 50
core_functions:
- description: >-
    Squalene synthase: catalyses the NAD(P)H- and Mg2+-dependent reductive condensation of
    two molecules of farnesyl diphosphate to squalene (via presqualene diphosphate), the first
    committed step of sterol biosynthesis, at the endoplasmic reticulum membrane.
  molecular_function:
    id: GO:0051996
    label: squalene synthase [NAD(P)H] activity
  directly_involved_in:
  - id: GO:0006695
    label: cholesterol biosynthetic process
  locations:
  - id: GO:0005789
    label: endoplasmic reticulum membrane
  supported_by:
  - reference_id: PMID:10896663
    supporting_text: through a reductive dimerization of two farnesyl diphosphate (FPP)
  - reference_id: file:human/FDFT1/FDFT1-uniprot.txt
    supporting_text: Catalyzes the condensation of 2 farnesyl pyrophosphate (FPP)
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO
    terms
  findings: []
- id: GO_REF:0000024
  title: Manual transfer of experimentally-verified manual GO annotation data to orthologs
    by curator judgment of sequence similarity
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location
    vocabulary mapping, accompanied by conservative changes to GO terms applied by
    UniProt
  findings: []
- id: GO_REF:0000052
  title: Gene Ontology annotation based on curation of immunofluorescence data
  findings: []
- id: GO_REF:0000117
  title: Electronic Gene Ontology annotations created by ARBA machine learning models
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:10896663
  title: Crystal structure of human squalene synthase. A key enzyme in cholesterol
    biosynthesis.
  findings:
  - statement: >-
      Human squalene synthase catalyses biosynthesis of squalene through reductive
      dimerization of two FPP molecules; conversion of FPP to squalene is the first
      committed step in cholesterol formation.
    supporting_text: through a reductive dimerization of two farnesyl diphosphate (FPP)
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Human SQS crystal-structure and catalysis paper; directly establishes the core
      molecular function (EC 2.5.1.21) and the first-committed-step role.
- id: PMID:23864651
  title: The identification of novel proteins that interact with the GLP-1 receptor
    and restrain its activity.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      GLP-1R interactome (MYTH Y2H + CO-IP). FDFT1 is one of many co-detected interactors;
      supports only a bare GO:0005515 protein-binding annotation, not SQS function.
- id: PMID:25910212
  title: Widespread macromolecular interaction perturbations in human genetic disorders.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      Interactome-scale edgotyping study; source of a generic protein-binding IPI for FDFT1.
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      HuRI binary interactome (Y2H); source of multiple bare GO:0005515 protein-binding calls
      for FDFT1, many with ER/membrane partners but no defined molecular function.
- id: PMID:8474436
  title: 'Conservation between human and fungal squalene synthetases: similarities
    in structure, function, and regulation.'
  findings:
  - statement: >-
      Squalene synthetase (EC 2.5.1.21) is a major control point of isoprene and sterol
      biosynthesis; the human enzyme is a C-terminal membrane-spanning ~50 kDa protein and
      functionally complements sterol-deficient (ERG9) yeast.
    supporting_text: is thought to represent a major control point
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Cloning/characterization of human hepatic squalene synthase; establishes conservation,
      membrane topology, and role in sterol biosynthesis (basis of the TAS annotations).
- id: Reactome:R-HSA-1655850
  title: Expression of Farnesyldiphosphate Farnesyltransferase (FDFT1, Squalene Synthase)
  findings: []
- id: Reactome:R-HSA-191402
  title: Reduction of presqualene diphosphate to form squalene
  findings: []
- id: Reactome:R-HSA-191405
  title: Two FAPP molecules dimerize to form presqualene diphosphate
  findings: []
- id: file:human/FDFT1/FDFT1-uniprot.txt
  title: UniProtKB P37268 (FDFT_HUMAN) entry - Squalene synthase
  findings: []

FDFT1

Gene Description